The objectives of this proposal are to investigate the unique pathogenetic routes to discrete forms of pancreatic ductal cancers. The principal investigator, Dr. Sunil R. Hingorani, is a physician-scientist whose long-term interests are in applying fundamental research discoveries toward the improved care of pancreatic cancer patients. Now the fourth leading cause of cancer-related deaths in this country, PDA is a disease with a rising incidence and unabated mortality. The underlying premise of these efforts holds that a comprehensive understanding of the pathogenesis of pancreatic cancer requires the generation of animal models that faithfully recapitulate the entire progression scheme beginning with the earliest preinvasive state. Indeed, given the penchant for this disease to metastasize very early in its course, the ability to intervene meaningfully likely requires identification and treatment from its very inception. We have developed strains of mice that faithfully recapitulate the full spectrum of disease from pancreatic intraepithelial neoplasias (PanINs) to conventional PDA. Most recently we have developed a murine model of mucinous cystic neoplasms (MCNs) which progress to invasive carcinomas. Although histologically very similar in their end stages, these two routes to invasive disease have dramatically different clinical and prognostic implications for patients. Nevertheless, they appear to involve the same overall mutational spectra in their respective genetic progression schemes. Thus the basis for these profound differences are unexplained and potentially critical for the detection and eradication of these cancers. The studies described herein are designed to investigate the molecular basis for these differences. It can be reasonably hoped that the insights gleaned from these endeavors will aid efforts to develop effective early detection methods and identify and test therapeutic strategies for patients. The NCI Pancreatic Cancer Progress Review Group Report identified development of gene-based animal models of pancreatic cancer as a top research priority. The research described in this application specifically addresses this priority and is 100% relevant to pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreas cancer kills every patient it afflicts. Impossible to treat, difficult to study, severely underfunded and under-researched, the disease presents an insidious tangle of circumstances that has resulted in no meaningful improvement in survival over the past four decades. We have developed genetically engineered animal models of distinct types of pancreas cancer that together should help us identify unique points of vulnerability for the development of new treatments.